Hemoglobin-digesting parasites, including the malaria parasites Plasmodium falciparum and Plasmodium vivax generate significant concentrations of free ferrous iron in the form of unbound heme, a side product of hemoglobin degradation. The presence of these chemically reactive forms of iron present an opportunity for parasite targeted drug delivery as free forms of ferrous iron are exceedingly rare in healthy tissue and cells. We have developed a ferrous iron targeted drug delivery technology for delivery of therapeutics to the malaria parasites or, more broadly, to any biological compartment containing unbound ferrous iron. Drug delivery strategies have scarcely been investigated in anti-parasitic therapy but these approaches have the potential to target parasites selectively, protecting the patient from exposure to active drug species and possibly allowing the use of a broader range of therapeutics safely. The drug delivery system consists of a 1,2,4-trioxolane ring system as an iron(II)-sensing 'trigger'moiety and a retro-Michael linker to which the partner drug is attached and ultimately released via a ?-elimination reaction. The chemical design is such that drugs from a wide swath of chemical and therapeutic target space can in principle be delivered using the approach. In preliminary work, we synthesized prototypical delivery systems and demonstrated using a chemical biological approach successful drug delivery to cultured intra-erythrocytic P. falciparum parasites. The goals of the proposed research are to evaluate iron(II)-targeted drug delivery systems in animals, and to optimize the existing delivery chemistry for reduced complexity and more rapid drug release kinetics. The realization of these objectives could significantly impact the field of antiparasitic chemotherapy specifically, and drug delivery more generally. PUBLIC HEALTH RELEVANCE: Malaria causes over a million preventable deaths annually, primarily among children in developing regions of the world. Current World Health Organization (WHO) recommended treatment for malaria involves combinations of an artemisinin-based therapy with a second agent of a distinct therapeutic class. This proposal seeks to establish proof-of-principle in animals for a new approach to deliver artemisinin combination therapy. Specifically, the proposed therapeutic strategy involves parasite-specific delivery of the second partner drug only after entry into the malaria parasite and only after the artemisinin-like activity has been conferred. Using this new approach, it should be possible to prevent patient exposure to the partner agent in its native form and this in principle could improve the safety profiles of existing antimalarial drugs or enable the widespread use of existing drugs that while effective, have serious side effects.